The purpose of this multidisciplinary Research Program is to elucidate the molecular/metabolic basis of Alzheimer's disease (AD) and to direct research toward both symptomatic and preventative treatment. These studies have developed from our original observation (Pettegrew et al 1984) that AD brain contains elevated levels of a class of molecules, phosphomonoesters (PME), that are normally found in high abundance only in developing brain in association with neuritic sprouting. It is remarkable that a degenerative disease should bear such striking molecular/metabolic resemblance to the normal developing brain. The relationship between neuritic sprouting and PME levels will be further examine in Project 5. Further preliminary studies demonstrate the PME have striking conformational similarities with the neurotransmitter L-glutamate, have electrophysiological activity at hippocampal CA1 pyramidal cells and can disrupt the structure and dynamics of phospholipids typically found on the cytoplasmic face of membranes. These findings all suggest that PME are neurobiologically active. Further detailed qualitative and quantitative analyses of the individual PME and phospholipids (Project 1-A), phospholipid enzymes (Project 1-B), neuropharmacological properties of the PME (Projects 1-D, 2, 4) and structural studies of the PME (Project 1-D) are mandated. It is possible that brief episodes of hypoxia or ischemia could activate phospholipase C or phosphodiesterases in individuals genetically predisposed to AD producing elevated levels of PME. The relationship between hypoxia/ischemia and elevated protein (beta-AP) that accumulates in AD and Down's Syndrome (DS) might have a neurotrophic role in vivo and perhaps could be causally linked to the neuritic sprouting demonstrated in AD. For this reason we are proposing studies to investigate the molecular biology of several of the beta-AP fragments, to investigate strategies for non-invasively imaging beta-amyloid deposits in vivo, and investigate possible metabolic linkages between the PME and beta- amyloid precursor protein (Project 2). Since all DS patients over the age of 40 have abundant SP but only 15-30% show signs of dementia, a longitudinal in vivo 31P NMR study of DS patients from age 10 to over 40 could provide insights into the relative roles of the PME and beta-AP in the dementia of DS with implications for AD (Project 3). A companion NIA funded longitudinal in vivo 31P NMR study of AD patients is ongoing (Jay W. Pettegrew P.I.).